Antibodies designed as effective cancer vaccines

Antigen/antibody complexes can efficiently target antigen presenting cells to allow stimulation of the cellular immune response. Due to the difficulty of manufacture and their inherent instability complexes have proved inefficient cancer vaccines. However, anti-idiotypic antibodies mimicking antigens have been shown to stimulate both antibody and T cell responses. The latter are due to T cell mimotopes expressed within the complementarity-determining regions (CDRs) of antibodies that are efficiently presented to dendritic cells in vivo. Based on this observation we have designed a DNA vaccine platform called ImmunoBody™, where cytotoxic T lymphocyte (CTL) and helper T cell epitopes replace CDR regions within the framework of a human IgG1 antibody. The ImmunoBody™ expression system has a number of design features which allow for rapid production of a wide range of vaccines. The CDR regions of the heavy and light chain have been engineered to contain unique restriction endonuclease sites, which can be easily opened, and oligonucleotides encoding the T cell epitopes inserted. The variable and constant regions of the ImmunoBody™ are also flanked by restriction sites, which permit easy exchange of other IgG subtypes. Here we show a range of T cell epitopes can be inserted into the ImmunoBody™ vector and upon immunization these T cell epitopes are efficiently processed and presented to stimulate high frequency helper and CTL responses capable of anti-tumor activity.Key words: DNA vaccines, cancer vaccines, melanoma, CTL, helper T cells     

New observations and reinterpretation on the enigmatic taxon Colombitherium (?Pyrotheria,Mammalia) from Colombia

Abstract: The controversial taxon Colombitherium tolimense (Mammalia) (probably Late Eocene in age) from Colombia, although known for nearly 40 years, still bears much mystery. Aside from the problematic ordinal attribution of the holotype and only specimen, its determination as an upper or lower jaw remains a highly debated issue. New observations include the presence of a contact facet on the distal face of the most posterior tooth, which indicates that the fragmentary jaw preserves three premolars and two molars; the M3, unpreserved but present, being most probably reduced. This new interpretation completely fits the morphology of the teeth. Furthermore, the shape of these latter and the deeper wear encompassed by their lingual part relative to the labial one is typical of upper dentition. This is in agreement with the internal curving of the roots of the anterior premolars and with several other arguments that lead interpreting the holotype of C. tolimense as a maxillary bearing P2‐M2. This new interpretation deepens the morphological gap between Colombitherium and other pyrotherians (except Proticia) and challenges further its referral to Pyrotheria. The peculiar morphology of Colombitherium relative to other pyrotherians is indeed striking. In fact, Colombitherium has nothing in common with pyrotherians but bilophodont cheek teeth, a feature largely widespread in placental mammals. It is here referred to ?Pyrotheria until additional evidence of its relationships is known. Associated with the putative removal of Proticia from Pyrotheria as argued by some authors, the hypothetical removal of Colombitherium from the order would adjust the widely accepted assumption that the pyrotherian bilophodont cheek teeth originated from bunodont cheek teeth. It would also make an origin from lophodont forms plausible. This in turn would have critical relevance, especially to the hypothesis that pyrotherians are notoungulates.     

Azygos Vein Lead Implantation For High Defibrillation Thresholds In Implantable Cardioverter Defibrillator Placement

Evaluation of defibrillation threshold is a standard of care during implantation of implantable cardioverter defibrillator. High defibrillation thresholds are often encountered and pose a challenge to electrophysiologists to improve the defibrillation threshold. We describe a case series where defibrillation thresholds were improved after implanting a defibrillation lead in the azygos vein.     

Polyhydroxylated steroid compounds from the Far Eastern starfish Distolasterias nipon

Two new steroid glycosides: distolasteroside D6, (24S)-24-O-(beta-D-xylopyranosyl)-5alpha-cholestane-3beta,6alpha,8,15beta,16beta,24-hexaol, and distolasteroside D7. (22E,24R)-24-O-(beta-D-xylopyranosyl)-5alpha-cholest-22-ene-3beta,6alpha,8,15beta,24-pentaol were isolated along with the previously known distolasterosides D1, D2, and D3, echinasteroside C, and (25S)-5alpha-cholestane-3beta,4beta,6alpha,7alpha,8,15alpha,16beta,26-octaol from the Far Eastern starfish Distolasterias nipon. The structures of new compounds were elucidated by NMR spectroscopy and MALDI TOF mass spectrometry. Like neurotrophins, distolasterosides D1, D2, and D3 were shown to induce neuroblast differentiation in a mouse neuroblastoma C 1300 cell culture.     

Steroidal polyols from Far Eastern starfish Henricia sanguinolenta and H. leviuscula leviuscula

Two new asterosaponins, (20R)-3-O-beta-D-(2-O-methylxylopyranosyl)-24-propylcholest-4-ene-3 beta,6 beta, 8, 15 alpha, 16 beta, 29-hexaol (sanguinoside A) and (20R,24S)-3-O-beta-D-(2,3,4-tri-O-methylxylopyranosyl)-5 alpha-cholestane-3 beta, 4 beta, 6 beta, 8, 15 alpha, 24-hexaol (sanguinoside B), were isolated from two species of Pacific Far Eastern Starfish Henricia sanguinolenta and H. leviuscula leviuscula, collected in the Sea of Okhotsk. Both glycosides contain aglycones with pentahy-droxysteroid nuclei of similar structures, which are substituted at the 3-hydroxy group with differently methylated beta-D-xylosyl residues. Sanguinoside A has an unusual structure of its aglycone side chain, whereas sanguinoside B has a unique permethylated carbohydrate chain. In addition, laevisculoside G, a known glycoside, was identified in the H. leviuscula starfish. The structures of the isolated glycosides were established by interpreting their spectral data and by comparing their spectral characteristics with those of known compounds. The English version of the paper. Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.     

Halogenated diterpenoids from the red alga Laurencia nipponica

Chemical compositions of three collections of the red alga Laurencia nipponica from the western part of the Sea of Japan were studied. One of them contained a series of the previously known sesquiterpenoids. Another one gave C15 bromoallene ethers, predominantly. Finally, two new halogenated diterpenes, 15-bromoparguer-9(11)-ene-16-ol and 15-bromoparguer-7-ene-16-ol, were isolated from the third collection of the same species. Structures of these diterpenoids were established by 1D and 2D NMR (1H-1H COSY, DEPT, HMQC, HMBC and NOESY) along with molecular calculations for conformations having lowest energies and mass spectroscopy. Diversity and variability of halogenated secondary metabolites in L. nipponica were discussed.     

Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations

The current model for reverse cholesterol transport proposes that HDL transports excess cholesterol derived primarily from peripheral cells to the liver for removal. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic contribution to plasma HDL-C levels, we generated an adenovirus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GFP in vivo to the liver. Compared with mice injected with control AdV, infusion of rABCA1-GFP-AdV into C57Bl/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepatocytes isolated 1 day after rABCA1-GFP-AdV infusion. Hepatic ABCA1 expression in C57Bl/6 mice (n = 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150-300% (P < 0.05 all). ABCA1 expression led to significant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reductase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver. These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing pathways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDL-C.